3-4-dihydrobenzo(b) (1,7)naphthyridin-1(2h)-ones

ABSTRACT

Compounds of the formula:   WHEREIN R is hydroxy, phenoxy, chloro, amino, or di(lower)alkylamino (lower)alkylamino; R1 is hydrogen or acetyl; R2 is hydrogen or methoxy; R3 is hydrogen or methoxy; and R4 is hydrogen, methoxy or dimethylamino are antispasmodic agents abolishing spastic contractions and lowering hypertonicity of the ileum and colon.

United States Patent Watson, Jr.

1 51 3,700,673 Oct. 24, 1972 [54] 3-4-DIHYDROBENZO(B)(1,7)NAPHTHYRIDIN-l(2H)-ONES [72] Inventor: Edward John Watson, Jr.,West Chester, Pa. 4

22 Filed: Feb. 12,1971

[21] Appl.No.: 115,042

[52] US. Cl. ..260/287 R, 260/288 A, 260/288 R, 260/293.8l 424/258 51 11111. C1. ..C07d 39/00 [58] Field of Search ..260/288 R, 288 A, 287 R[56] References Cited UNITED STATES PATENTS 3,232,945 2/1966 Sigal..260/288 R 3,580,915 5/1971 Wolf ..260/288 R FOREIGN PATENTS 0RAPPLICATIONS 1,022,593 1/1958 Gennany ..260/288 R 7 OTHER PUBLICATIONSKempter et al., Ber., Vol 98, pp. 420- 421 (1965). Corbett et al., Chem.Abst., Vol. 60, Co]. 547lg (1964).

Primary Examiner-Donald G. Daus Attorney-Bradford S. Allen [57] ABSTRACTCompounds of the formula:

- spastic contractions and lowering hypertonicity of the ileum andcolon.

14 Claims, No Drawings 3-4-DIHYDROBENZO(B) (l ,7)NAPHTHYRIDIN-1(2H)-ONES This invention relates to chemical compounds. Moreparticularly it is concerned with certain 3,4 dihydrobenzo{b][1,7]naphthyridin-l(2l-l)-ones of the formula:

wherein R is hydroxy, phenoxy, chloro, amino or di(lower)alkylamino(lower) alkylamino; R is hydrogen or acetyl; R ishydrogen or methoxy; R is hydrogen or methoxy and R is hydrogen, methoxyor dimethylamino. These compounds are antispasmodic agents. They arecapable upon intravenous administration of abolishing spasticcontractions and lowering hypertonicity of the ileum and colon inducedby morphine in the dog. While they share a common antispasmodicproperty, they differ from each other in degree of activity as might beexpected. A representative member, S-phenoxy 3,4-dihydrobenzo[b][ 1,7]naphthyridin- 1 (2H )-one, administered intravenously at a dose of from10-20 mg/kg in a vehicle composed of parts polyethylene glycol ofaverage molecular weight 300, 3 parts of ethanol and 2 parts water todogs counteracted spastic contractions and decreased hypertonicity ofthe ileum and colon induced by morphine.

The method for making the compounds of this invention consists inreacting an aniline with 2,3-dioxo-4- piperidinecarboxylate to produce a3, 4-dihydro-5- hydroxybenzo[b][ l ,7]naphthyridin- 1 (2H)-one whosehydroxyl can be replaced by groups such as chloro in known fashion andthat, in turn, by amino in conventional manner. Acetylation isaccomplished with acetic anhydride or acetyl chloride.

Illustrative syntheses according to the foregoing scheme are appended inthese examples:

EXAMPLE 1 A. Ethyl 2,3-Dioxo-4-piperidinecarboxylate A few crystals ofiodine and two grams of HgCl were introduced into a mixture of benzene(2 l.) and ethanol (280 ml). Sodium methoxide (108 g, 2.0 moles) wasadded with stirring. A mixture of 2-pyrrolidone 17.2 g, 2.0 moles) anddiethyl oxalate (292 g, 2.0 moles) was introduced. Slight exothermicitywas observed. The reaction mixture was refluxed for 24 hours. It wasacidified with 320 ml of 1:1 l-lCl. The hot benzene was decanted, thesalt and water were mixed with fresh boiling benzene, and the benzenewas decanted. This extraction with boiling benzene was done three times.The extracts were combined and filtered by gravity. The filtrate wasconcentrated under reduced pressure to approximately 1.5 I. This wasconcentrated on a steam bath to approximately 600 ml. On coolingovernight a solid (m.p. l48-l5 1) was obtained.

B. 3,4-Dihydro-5-hydroxybenzo[b][ l ,7 ]naphthyridin- 1 (2H )-one In a 5liter three-neck flask was placed 370 g (2.0 moles) of A., 186 g (2.0moles) of aniline, 2 liters of toluene and drops of concentrated HCl.The flask was fitted with stirrer, thermometer, dropping funnel andDean-Stark trap with condenser. Water was removed by azeotropicdistillation with toluene until 35.5 ml had been collected. TheDean-Stark trap was removed and the condenser was set for distillation.Toluene was distilled out of the flask while 2 liters of Dowtherm wereadded by means of the dropping funnel. The reaction mixture was thenheated at reflux (above 250) for 1 k hours. Upon allowing the darksolution to cool, the product crystallized. The solid was filtered offand washed with hexane. The yield of crude product was 380 g (89percent). The crude material was recrystallized from one liter ofethylene glycol to give 361 g (95 percent recovery).

EXAMPLE 2 2-Acetyl-3,4-dihydro-5-hydroxybenzo[b][ 1 ,7 ]naph thyridinl(2H)-'one The compound of Example 1, B g, 0.234 mole) was suspended inacetieanhydride (150 ml). The reaction mixture was heated to reflux andacetic acid (200 ml) was introduced. The content of the flask wasrefluxed for 3 hours. Acetic anhydride (30 ml) was introduced andrefluxing was continued for another 3 hours. The reaction mixture waspoured into ice water after cooling. The solid that formed was filteredand washed with water and ethanol. Thus 52 g, m.p. 275-277 (Mel-Temp)were obtained. Yield: 86.6 percent. A purified sample, m.p. 292293, wasprepared by recrystallizing from acetic acid.

EXAMPLE 3 means of a heating mantle and refluxed for 2 hours.

The solution was allowed to cool and then was poured into 2 l. of cold10 percent NaOH solution with good stirring. An additional 1.5.1. ofwater was added and the material was thoroughly stirredv until the oilthat initially formed had become a crystalline precipitate.

The tan solid was filtered off and washed with water and finally withdry ether. In this way was obtained g (87 percent yield) of crudeproduct, m.p. 247-255. The crude material was recrystallized with 400 mlof dimethyl-formamide (Darco) yielding 61 g, m.p. 270-27l (partialmelting 266) (70 percent over-all yield).

EXAMPLE 4 5-Chloro-3,4-dihydrobenzo[b] [1,7] naphthyridinl(2H)-one In a2-1. three-neck flask equipped with stirrer, thermometer and distillingcondenser, was placed g (0.39 mole) of the compound of Example 1, B. and700 ml of POCl The suspension was very gradually heated to 70 by meansof a steam bath and maintained at this temperature for 30 minutes. Thereaction mixture was allowed to cool somewhat, and excess POCl wasremoved by distillation at reduced pressure.

- addition of 1,500 ml of ice water while the reaction flask was cooledby means of an ice bath. The ice bath was removed and the temperatureofthe reaction mixture gradually rose from to 30. At this point a waterbath was used to prevent the temperature of the mixture from exceeding30.35. When the exothermic reaction was over, the mixture was allowed tostir overnight. The mixture was filtered and the small amount of darkprecipitate was washed with water.

The dark solution was made basic with concentrated Nl-l Ol-l (500 ml),and a solid precipitated. The solid was filtered off and washed withwater. The partially dry pasty solid was recrystallized from 635 ml ofdimethylformamide. The recrystallized material weighed 69 g (76 percentyield), m.'p. 25 125 3.

EXAMPLE 5 3 ,4-Dihydro-5-hydroxy-9-methoxybenzo[b][ 1 ,7] naphthyridin-1 (21-1 )-one A. Ethyl 3-( 2-Methoxyphenylimino)-2-oxoisonipecotate In a1 liter Erlenmeyer flask was placed 25 g (0.2 mole) of o-anisidine and37 g (0.2 mole) of ethyl 2,3- dioxoisonipecotate. One drop of conc. HClwas added and the mixture was heated on the steam bath for two hours.The viscous liquid was allowed to cool. The resultant solid was treatedwith 250 ml of hot isopropanol, the mixture was allowed to cool and thenfiltered. After drying overnight at 60, the yellow solid weighed 38 g(66 percent yield), m.p. 1 1 l-l14 (with dec.).

B. 3 ,4-Dihydro-5-hydroxy-9-methoxybenzo[ b][ l,7] naphthyridine- 1(2H)-one In a 1 liter flask fitted with stirrer, reflux condenser andthermometer, was placed 38 g (0.13 mole) of the above anil and 200 ml ofDowtherm A. The suspension was rapidly heated to reflux and maintainedat the reflux temperature for 45 minutes. Upon cooling, a solid formedwhich was filtered off and washed with absolute ethanol. The yield ofcrude product was 28 g (88 percent). It was purified byrecrystallization from 300 ml of dimethylformamide using Darco.

EXAMPLE 6 3,4-Dihydro-7,8-dimethoxy-5-hydroxybenzo[b] l,7] naphthyridin-1 (2H )-one In a 3 liter three-neck flask equipped with stirrer,dropping funnel, thermometer and Dean-Stark trap, was placed 153 g (1.0mole) of aminoveratrole, 185 g (1.0 mole) of ethyl2,3-dioxoisonipecotate, 1 liter of toluene and 2 drops of conc. I-ICl.The reaction mixture was heated to reflux and water was removed byazeotropic distillation. After the theoretical amount of water (18 ml)had been collected in the DeanStark trap, the mixture was allowed toreflux for 2 hours. At this point the reaction was interrupted and theDean- Stark trap replacedwith a condenser set for distillation. Toluenewas gradually distilled off while 1 liter of Dowtherm A was added to thereaction flask. The temperature of the mixture gradually rose to theboiling point of Dowtherm A (255). The mixture was refluxed for 2 hoursand then allowed to cool overnight.

The dark solid that precipitated was filtered off and washed withDowtherm A and then with absolute ethanol. The crude material wasrecrystallized from 3 liters of dimethylformamide yielding 133 g (41percent yield), m.p. 314-3l8(dec.).

mole) of p-anisidine, 74 g (0.4 mole) of the compound of Example 1, A.,400 ml. of toluene and 2 drops of concentrated HCl. The flask wasequipped with stirrer, thermometer dropping funnel and Dean-Stark trapwith condenser. Water was removed by azeotropic distillation.(7.2 ml).Dowtherm A, 400 ml, was added through the dropping funnel while toluenewas distilled out of the reaction flask. The mixture was then refluxedfor 1-% hours. Upon cooling, the solid was filtered off and washedconsecutively with dimethylformamide, ethanol and ether. The yield ofproduct was 38 g (39 percent), m.p. dec. 360.

B. 5-Chloro-3,4-dihydro-7-methoxybenzo[b][ 1 ,7] naphthyridinl(2I-I)-one A 3 liter three-neck flask was fitted with stirrer,thermometer, Claisen adapter and distillation condenser. In the flaskwas placed 50 g (0.205 mole) of A. and 500 ml of POCl This mixture washeated cautiously by means of a steam bath to 50. The reaction becameexothermic and the temperature rose to 90. The reaction mixture was thenallowed to cool to 70 and maintained at this temperature for 1 hour.

Excess POCI was removed by distillation at reduced pressure. Theresidual material was decomposedbythe rapid addition of 2 liters of icewater. The insoluble solid was filtered off and washed with water. Thesolid was placed in an Erlenmeyer flask with 1 liter of water.Concentrated HCl, -50 ml, was added. A homogeneous solution resulted.The solution was filtered, cooled and made basic with aqueous ammonia. Abrown solid formed. This was'filtered off, washed with water and driedyielding g (theoretical yield was 54 g).

Recrystallization of this from dimethylformamide gave a material withm.p. 301304.

EXAMPLE 8 2-Acetyl-5-chloro-3,4-dihydrobenzo[b][ 1,7] naphthyridin-l(21-1 )-one In a 3 liter three-neck flask, equipped with stirrer,thermometer, Claisen adapter and distillation condenser, was placed 82 g(0.3 mole) of the compound of Example 2 and 700 ml of POCI This mixturewas allowed to stir for 1 hour during which time the temperature rosefrom 25 to 35. The reaction mixture was heated to 50 (steam bath) andallowed to cool for 25 minutes. Then it was heated to 60 and allowed tocool for 1' hour. Excess POCI was removed at reduced pressure. The solidresidue was decomposed with 1,500 ml EXAMPLE 9 5-Amino-3,4-dihydrobenzo[b] 1(2l-l)-one In a 1 liter three-neck flask was placed93 g (0.4 mole) of the compound of Example 4 and 320 ml of moltenphenol. The flask was fitted with stirrer, reflux condenser, thermometerand gas addition tube. The reaction mixture was heated to 95 and ammoniawas passed in until the solution was saturated. The solution was thenrefluxed for 4 hours (180) while slow addition of ammonia was continued.

The solution was allowed to cool and then was poured into 1,500 ml ofanhydrous ether with good stirring. The ether was decanted from theslightly sticky solid and fresh ether was added. Filtration gave 150 gof the unstable hydrochloride. This solid was suspended in 2 liters ofwater and stirred to form the free base, 66 g (78 percent yield).

The crude product was recrystallized from 600 ml of dimethylformamide toyield 37 g, m.p. 306308.

EXAMPLE A. 3,4dihydro-7dimethylamino-5-hydroxybenzo[b] [1,7]naphthyridin- 1 21-1 )-one In a 3 liter three-neck flask was placed 185g (1.0 mole) of the compound of Example 1, A., 136 g (1.0 mole) ofp-dimethylaminoaniline, 1 liter of toluene and 2 drops of concentratedHCl. The flask was fitted with stirrer, addition funnel, thermometer andDean-Stark trap with condenser. The mixture was heated by means of aheating mantle and Water was removed by azeotropic distillation. Twohours were required to remove the theoretical amount of water 18 ml).

The Dean-Stark trap with condenser was removed and replaced by acondenser set for distillation. One liter of Dowtherm A was graduallyadded to the reaction flask while toluene was removed by distillation.The mixture was then refluxed (255) for l- /z hours. It was then allowedto cool to 40. The solid that formed was filtered off and washed firstwith benzene and then with ethanol. The dried brown solid weighed 205 g(80 percent Yield) m.p. 3163 18 (dec.).

Recrystallization of 40 g of the crude solid from 750 ml ofdimethylformamide gave 26 g (65 percent recovery), m.p. 3l6-318(dec.).

B. 5Chloro-7-dimethylamino-3,4-dihydrobenzo[b][ 1,7] naphthyridin- 1(2I-I)-one A 2 liter three-neck flask was fitted with stirrer, refluxcondenser and thermometer. In the flask was placed 170 g (0.66 mole) ofA. and one liter of POCI The stirred suspension was slowly heated to 70.At this point the reaction appeared to be exothermic, the temperaturegoing to 85 after removal of the heat source (steam bath). The reactionmixture became viscous. After the temperature returned to 70, heatingwas used to maintain this temperature for 45 minutes.

Excess POCI was distilled out of the reaction flask under reducedpressure. To the residual solid was added 2 liters of ice water. Thematerial turned a dark red color and appeared partially to dissolve. Themixture was filtered and the filtrate was made basic with NH.,OH. Thesolid was formed was filtered'ofi, washed with water and allowed to drygiving 255 g of dark red solid.

[ 1,7 ]naphthyridin- This solid was dissolved in hot water, treated withDarco and filtered hot. To the filtrate was added concentrated NI-LOl-Iuntil basic. The yellow precipitate that formed was filtered off.Recrystallization from dimethylformamide gave a m.p. (dec.) 307.

C. 5Amino-3,4-Dihydro-7dimethylaminobenzo[b]f 1,7]naphthyridin-1(2H)-one Ninety-four g (0.34 mole) of B. was placed in a 2liter three-neck flask equipped with stirrer, thermometer, refluxcondenser and ammonia gas inlet tube. To the flask was added 675 ml ofmolten phenol. The suspension was heated to and saturated with gaseousammonia. The temperature was then gradually raised to (refluxingphenol). The reaction mixture was maintained at this temperature for 4-%hours while a slow stream of ammonia was passed through.

The reaction mixture was then cooled to room tem perature and pouredinto two liters of ether (vigorous stirring). The solid that formed wasfiltered and washed well with ether. The precipitate was dissolved inwater and a small amount of insoluble material was filtered off. Thefiltrate was made basic with ammonia. The resulting precipitate wasfiltered off and washed with water giving 86 g (96 percent yield).

Recrystallization from dimethylformamide gave m.p. 335-337 with dec.

EXAMPLE 1 l 3,4-Dihydro-5-(2dimethylaminoethylamino)ben2o[ b][ 1,7]naphthyridin- 1 (2H )-one In a 1 liter one-neck flask was placed 46 g(0.2 mole) of the compound of Example 4, 53 g (0.6 mole) of N,N-dimethylethylenediamine and 500 ml of dimethylformamide. The mixturewas refluxed for 24 hours. Dimethylformamide and the excess di-amine wasremoved on a rotary evaporator yielding a dark oil. This oil wasdissolved in water and some aqueous ammonia was added. Any solid thatformed at this point was filtered off. The water layer was extractedwith chloroform in three 100 ml portions. The chloroform was removed bydistillation leaving a dark oil. To this oil was added 250 ml ofisopropanol. A yellow solid soon appeared. This was filtered off, washedwith isopropanol and dried yielding 16 g (21 percent).

Recrystallization of 38 g of this product from isopropanol (20 25 mg/g)yielded 28 g. m.p. 206-210 0 EXAMPLE l25-Amino-3,4-dihydro-7-methoxybenzo[b][ l ,7] naphthyridin-l (2I-I)-oneIn a 3 liter three-neck flask, equipped with stirrer, thermometer,reflux condenser and ammonia gas inlet tube, was placed 57 g (0.218mole) of the compound of Example 7, B. and 360 ml of molten phenol. Thismixture was heated to 100 and saturated with gaseous ammonia. Thereaction mixture was then heated to reflux (180) and maintained at thistemperature for 5 hours while a slow stream of gaseous ammonia was beingadded. The reaction mixture was then cooled to room temperature andpoured into 2 liters of anydrous ether (vigorous stirring). The solidthat formed was filtered off and washed with ether. This solid was thenadded to lliter of water with stirring. A precipitate soon appeared.After about 20 minutes the precipitate was fil- EXAMPLE 133-Diethylaminopropylamino)-3,4- dihydrobenzo[b]d[ l ,7] naphthyridin- 1(2H )-one In 1 liter round bottom flask was placed 46 g (0.2 mole) ofthe compound of Example 4, 78 g (0.6 mole) of N,N-diethyl-l,3-propanediamine and 200 m1 of ethyl celloso lve (2-ethoxy-ethanol). The mixture was refluxed overnight (18 hours). Thereaction mixture was cooled giving a voluminous solid. Enoughisopropanol was added so that the gelatinous solid could be broken upand filtered. The white solid so obtained, 8 g, was shown by IR to be ahydrochloride of the starting diamine and so was discarded.

The filtrate was concentrated on a rotary evaporator to a dark viscousresidue. About 500 ml of water was added. Some material dissolvedleaving a mushy solid. The mixture was filtrated and the solid washedwith water. When this solid was treated with isopropanol, it completelydissolved. Concentration of the isopropanol solution on the rotaryevaporator and triturating the residue with ethyl acetate gave 5.5 g offree base (8.4 percent yield).

The aqueous solution was extracted with three 250 ml portions ofchloroform. Concentration in the rotary evaporator gave a thick, veryviscous liquid. About 300 ml of water was added and this was removedbyway of the rotary evaporator so that residual diamine startingmaterial might be eliminated by steam distillation. Addition of 250 mlof isopropanol to the viscous residue and seeding gave g of a yellowishsolid (23 percent yield) m.p. l70-l74. 7

Concentration of the isopropanol filtrate and tritur'ation of theresidual material with ether and then with ethyl acetate gave anadditional 5 g of product (7.7 percent yield). Total yield was 25 g (38percent).

The free base was recrystallized from isopropanol l 6 ml/g) to give a 70percent recovery of purified free base, m.p. l74l76.

, 8 What is claimed is: 1. A compound of the formula:

wherein R is hydroxy, phenoxy, chloro, amino, or di(lower)alkylamino(lower) alkylamino; R is hydrogen or acetyl; R ishydrogen or methoxy; R is hydrogen or methoxy; and R is hydrogen,methoxy or dimethylamino.

2. The compound of claim 1 wherein R is hydroxy and R R R and R arehydrogen.

3. The compound of claim 1 wherein R is hydroxy, R .is acetyl and R Rand R are hydrogen.

4. The compound of claim 1 wherein Ris phenoxy, and'R R R and R arehydrogen.

5. The compound of claim 1 wherein R is chloro and 63 t i ip dli t i o li n l wherein R is hydroxy, R is methoxy and R R and R are hydrogen.

7. The compound of claim 1 wherein R is hydroxy, R is methoxy and R Rand R are hydrogen.

8. The compound of claim 1 wherein R is chloro, R, is methoxy and R Rand R are hydrogen.

9. The compound of claim 1 wherein R is chloro, R is acetyl and R R andR.. are hydrogen.

10..The compound of claim 1 wherein R is amino and R R R and R arehydrogen.

11. The compound of claim 1 wherein R is amino, R is dimethylamino andR,, R and R are hydrogen.

12. The compound of claim 1 wherein R is dimethylaminoethylarnino and RR R and R. are hydrogen.

13. The compound of claim 1 wherein R is amino, R is methoxy and R R andR are hydrogen.

14. The compound of claim 1 wherein R is dimethylaminoethylamino and R RR and R are hydrogen.

2. The compound of claim 1 wherein R is hydroxy and R1, R2, R3 and R4are hydrogen.
 3. The compound of claim 1 wherein R is hydroxy, R1 isacetyl and R2, R3 and R4 are hydrogen.
 4. The compound of claim 1wherein R is phenoxy, and R1, R2, R3 and R4 are hydrogen.
 5. Thecompound of claim 1 wherein R is chloro and R1, R2, R3 and R4 arehydrogen.
 6. The compound of claim 1 wherein R is hydroxy, R2 is methoxyand R1, R3 and R4 are hydrogen.
 7. The compound of claim 1 wherein R ishydroxy, R3 is methoxy and R1, R2 and R4 are hydrogen.
 8. The compoundof claim 1 wherein R is chloro, R4 is methoxy and R1, R2 and R3 arehydrogen.
 9. The compound of claim 1 wherein R is chloro, R1 is acetyland R2, R3 and R4 are hydrogen.
 10. The compound of claim 1 wherein R isamino and R1, R2, R3 and R4 are hydrogen.
 11. The compound of claim 1wherein R is amino, R4 is dimethylamino and R1, R2 and R3 are hydrogen.12. The compound of claim 1 wherein R is dimethylaminoethylamino and R1,R2, R3 and R4 are hydrogen.
 13. The compound of claim 1 wherein R isamino, R4 is methoxy and R1, R2 and R3 are hydrogen.
 14. The compound ofclaim 1 wherein R is dimethylaminoethylamino and R1, R2, R3 and R4 arehydrogen.